Methods and systems for using transcranial magnetic stimulation to enhance cognitive performance

ABSTRACT

Methods and systems are provided for using transcranial magnetic stimulation (TMS) to enhance cognitive performance of at least one subject. At least one neural circuit is located in the brain of the subject, which is activated when the subject performs a predetermined task. Functional magnetic resonance imaging maps may be used to scan and generate maps of the interested neural circuits so as to locate proper neural circuits responsible for a predetermined task. An electromagnetic coil is positioned over a region on the scalp of the subject corresponding to the at least one neural circuit in the brain of the subject. A transcranial magnetic stimulation is delivered from the coil to the region on the scalp of the subject to induce current to flow in the brain that causes neuronal depolarization in the brain and effectuates a change in the performance of the predetermined task by the subject.

BACKGROUND

The present invention generally relates to the use of transcranialmagnetic stimulation to enhance performance. More particularly, thepresent invention relates to methods and systems for using transcranialmagnetic stimulation to enhance cognitive performance of one or moresubjects.

For over a century, it has been recognized that electricity andmagnetism are interdependent (Maxwell's equations) (Bohning, 2000).Passing current through a coil of wire generates a magnetic fieldperpendicular to the current flow in the coil. If a conducting medium,such as the brain, is adjacent to the magnetic field, current will beinduced in the conducting medium. The flow of the induced current willbe parallel, but opposite in direction, to the current in the coil(Cohen et al., 1990; Brasil-Neto et al., 1992; Saypol et al., 1991; Rothet al., 1991). Thus, transcranial magnetic stimulation (hereinafter“TMS”) has been referred to as “electrode-less” electrical stimulationto emphasize that the magnetic field acts as the medium betweenelectricity in the coil and induced electrical currents in the brain.

TMS involves placing an electromagnetic coil on the scalp. Subjects areawake and alert. There is some discomfort, in proportion to the musclesthat are under the coil and to the intensity and frequency ofstimulation. Subjects usually notice no adverse effects except foroccasional mild headache and discomfort at the site of the stimulation.

High intensity current is rapidly turned on and off in the coil throughthe discharge of capacitors. This produces a time-varying magnetic fieldthat lasts for about 100-200 microseconds. The magnetic field typicallyhas a strength of about 2 Tesla (or 40,000 times the earth's magneticfield, or about the same intensity as the static magnetic field used inclinical MRI). The proximity of the brain to the time-varying magneticfield results in current flow in neural tissue.

The technological advances made in the last 15 years have led to thedevelopment of magnetic stimulators that produce sufficient current inbrain to result in neuronal depolarization. Neuronal depolarization canalso be produced by electrical stimulation, with electrodes placed onthe scalp (referred to as transcranial electric stimulation (“TES”)).Importantly, unlike electrical stimulation, where the skull acts as amassive resistor, magnetic fields are not deflected or attenuated byintervening tissue. This means that TMS can be more focal than TES.Furthermore, for electrical stimulation to achieve sufficient currentdensity in brain to result in neuronal depolarization, pain receptors inthe scalp must be stimulated (Saypol et al., 1991).

A striking effect of TMS occurs when one places the coil on the scalpover the primary motor cortex. A single TMS pulse of sufficientintensity causes involuntary movement. The magnetic field intensityneeded to produce motor movement varies considerably across individualsand is known as the motor threshold (Kozel et al., 2000; Pridmore etal., 1998). Placing the coil over different areas of the motor cortexcauses contralateral movement in different distal muscles, correspondingto the well-known homunculus. TMS can be used to map the representationof body parts in the motor cortex on an individual basis. Subjectively,this stimulation feels much like a tendon reflex movement. Thus, a TMSpulse produces a powerful but brief magnetic field which passes throughthe skin, soft tissue and skull and induces electrical current inneurons, causing depolarization which then has behavioral effects (bodymovement).

Single TMS over the motor cortex can produce simple movements. Over theprimary visual cortex, TMS can produce the perception of flashes oflight or phosphenes (Amassian et al., 1995). To date, these are the‘positive’ behavioral effects of single pulse TMS. Other immediatebehavioral effects are generally disruptive. Interference with, andperhaps augmentation of, information processing and behavior isespecially likely when TMS pulses are delivered rapidly andrepetitively. Repeated rhythmic TMS is called repetitive TMS (rTMS). Ifthe stimulation occurs faster than once per second (1 Hz) it is modifiedas fast rTMS.

rTMS at frequencies of around 1 Hz has been shown to produce inhibitionof the motor cortex. rTMS at higher frequencies of several minutes hasbeen shown to excite the underlying cortex for several minutes.Manipulations of frequency and intensity may produce distinct patternsof facilitation (fast rTMS) and inhibition (slow rTMS) of motorresponses with distinct time courses. These effects may last beyond theduration of the rTMS trains with enduring effects on spontaneousneuronal firing rates. Determining whether, in fact, lasting increasesand decreases in cortical excitability can be produced as a function ofrTMS parameters, and whether such effects can be obtained in areasoutside of the motor cortex, are of key importance.

As indicated above, TMS is generally safe with no side effects exceptmild headache in about 5% of subjects. However, higher frequency TMS canproduce seizures. With the publication of safety tables in 1998, therehave been no unintended seizures produced in the world (Wassermann etal., 1996b; Wassermann, 1997; Wassermann et al., 1996a). Animal studies,along with human post-mortem and brain imaging studies (Nahas et al.,2000a), have all failed to find any pathological effects of TMS(Lorberbaum & Wassermann, 2000).

TMS evoked motor responses result from direct excitation ofcorticospinal neurons at or close to the axon hillock. It is thoughtthat the TMS magnetic field induces an electrical current in superficialcortex. The TMS magnetic field declines exponentially with distance fromthe coil. This limits the area of depolarization with current technologyto a depth of about 2-cm below the brain's surface. Nerve fibers thatare parallel to the TMS coil (perpendicular to the magnetic field) aremore likely to depolarize than those perpendicular to the coil. It isthought as well that bending nerve fibers are more susceptible to TMSeffects than straight fibers (Amassian et al., 1995).

Conventional TMS coils are either round, or in the shape of a figureeight (Cohen et al., 1990). The figure eight designs are more focal thanthe round coils. Most coils are mere copper wire either alone or wrappedaround a solid metal core. Because most coils are inefficient, theyproduce heat as a byproduct. The solid coils are more efficient, withouta heating problem. Other manufacturers have used water cooling (Cadwell)or air cooling (Magstim) to deal with this issue. DARPA materialsscience research might drastically improve the current technology.

The peak effect of TMS can be localized to within less than a millimeterin terms of functional location. More work is needed in terms ofactually understanding the exact location of TMS effects (Bohning etal., 2001; Bohning et al., 1997). There is much debate about whether onecould devise an array of coils in such a way as to stimulate deep in thebrain without overwhelming superficial cortex.

Although current TMS technology has shown that it can interrupt andfacilitate many behaviors, several technical issues limit the field.Current coils are bulky and hard to focus. Because of the materialsused, they overheat and require large capacitors. It is not clearwhether one could stimulate deeper in the brain with current designs.Finally, TMS at present is limited to single TMS applications. There hasbeen virtually no work done on producing arrays of TMS coils that aredischarged in a coordinated fashion. Such an array would likely vastlyopen up new TMS vistas (including defense applications).

Most studies with TMS have shown that high frequency TMS can interrupt ahigher cognitive function. It is relatively easy to produce speecharrest by stimulating over the motor speech area (Broca's). Speecharrest occurs only for the moment of stimulation. With the MUSC team asconsultants, Drs. Stern and Lisanby at Columbia are using this ‘knockoutlesion’ ability of TMS to understand the neural circuits used inresponse to sleep deprivation. There are also some studies usingprecisely timed single pulse TMS for augmentation of function. But aswith the other potential applications, this requires precise timing(Grafinan, 2000). Precisely timing TMS bursts with stimulus presentationwould thus be more difficult to adapt to warfare conditions.

At the recent CAPS teaming workshop, two different Armed ForcesRepresentatives highlighted the need for ‘non-pharmacological’approaches to boosting cognitive performance. There is thus likely onlya small psychological hurdle for general warfighter acceptance of thesetechniques, should we succeed in finding ways of using TMS to enhanceperformance at baseline or following sleep deprivation. This generalwarfighter acceptance is remarkable given how revolutionary theseconcepts are, compared with the status quo. These representatives, whenasked why there might be such easy acceptance of TMS in the battlefield,responded that TMS made sense in terms of focal delivery of the neededchanges, without distribution throughout the whole body (e.g. lack ofside effects), and the ability to turn the device on and off withoutworry about lingering half-lives.

Thus, there is a huge need for radical new approaches (as highlighted inthe CAPS announcement). Human limitations on performance are now therate limiting aspects of most weapons systems and warfare capability.There is thus also likely easy acceptance of TMS, if the necessarybackground work shows that it can improve performance. The potentialimpact on DOD could thus be huge. If TMS is found to boost normalperformance, or even slightly restore performance in the face of sleepdeprivation, there will undoubtedly be many other potential military andnon-military applications. The design of man-portable TMS systems wouldprovide the foundation for a revolution in the field of TMS, withprofound impact on therapeutic applications as well.

Therefore, there is a need to develop new methods and systems that canutilize TMS to deliver stimulation to proper neural circuits of a livingbeing to enhance cognitive performance of the living being.

SUMMARY

According to a first aspect of the invention, methods for using TMS toenhance cognitive performance are provided. According to a firstembodiment, a method for enhancing cognitive performance includes thesteps of locating at least one neural circuit in the brain of a subject,which is activated when the subject performs a predetermined task,positioning an electromagnetic coil over a region on the scalp of thesubject corresponding to the at least one neural circuit in the brain ofthe subject, delivering a transcranial magnetic stimulation from thecoil to the region on the scalp of the subject, inducing a current toflow in the brain, causing neuronal depolarization in the brain, andeffectuating a change in the performance of the predetermined task bythe subject.

According to another embodiment, a method of using TMS to enhancecognitive performance in a plurality of subjects, such as human beings,includes the steps of dividing the plurality of subjects into groups,subjecting each of the groups into a first state and a second state,locating at least one neural circuit in the brain of a subject in thegroup corresponding to one of the first state and the second state,which is activated when the subject performs a predetermined task underone of the first state and the second state, positioning anelectromagnetic coil over a region on the scalp of the subjectcorresponding to the at least one neural circuit in the brain of thesubject, delivering a transcranial magnetic stimulation from the coil tothe region on the scalp of the subject, inducing a current to flow inthe brain, causing neuronal depolarization in the brain, andeffectuating a change in the performance of the predetermined task bythe subject under one of the first state and the second state. In oneembodiment, the first state is a state at which a subject is at rest,and the second state is a state at which a subject is sleep-deprived.fMRI can be utilized to identify different neural circuits associatedwith different subject at a state, wherein the neural circuits areactivated while a predetermined task is performed. TMS can then bedelivered to proper neutral circuits to restore and/or retrain thecircuits to enhance the performance.

According to yet another embodiment, a method of using TMS to enhancecognitive performance in at least one subject includes the steps ofduring a behavior individualized imaging of at least one cognitiveneural circuit, locating the at least one cognitive neural circuit,individually positioning an electromagnetic coil over a region on thescalp of the subject corresponding to the at least one cognitive neuralcircuit, and delivering a stimulation through the electromagnetic coilto the at least one cognitive neural circuit to affect the behaviorrelated to the at least one cognitive neural circuit. Individualizedimaging can be performed by an fMRI scanner, and the electromagneticcoil is associated with a TMS system, which are interleaved to providesynergistic stimulation(s).

In another aspect, a system of using TMS to enhance cognitiveperformance is provided. In one embodiment, the system includes meansfor locating at least one neural circuit in the brain of a subject,which is activated when the subject performs a predetermined task, anelectromagnetic coil that can be positioned over a spot on the scalp ofthe subject corresponding to the at least one neural circuit in thebrain of the subject, means for delivering a transcranial magneticstimulation from the coil to the spot on the scalp of the subject so asto induce a current to flow in the brain, cause neuronal depolarizationin the brain, and effectuate a change in the performance of thepredetermined task by the subject. The locating means includes an fMRIsystem that can be utilized to scan and generate maps of the interestedneural circuits so as to locate proper neural circuits responsible for apredetermined task. Additionally, the system includes a computer havinga CPU and one or more memory devices to, among other things, coordinatethe operation among the different parts of the system, optimize theoperation parameters such as TMS use parameters, and facilitate the TMSdelivering.

In another embodiment, a portable system of using TMS to enhancecognitive performance in at least one subject includes an energy source,such as a battery, a CPU, a database having fMRI maps of neural circuitscorresponding to a plurality of tasks stored therein, and a movableelectromagnetic coil. The CPU is electrically coupled to the energysource and communicates with the database, which is associated with amemory device of the CPU, or alternatively with a separate memorydevice, or both. The movable electromagnetic coil is electricallycoupled to the energy source and communicates with the CPU. Inoperation, when a subject is to perform a predetermined task, the CPUcommunicates with the database and selects one or more fMRI maps of oneor more neural circuits corresponding to the predetermined task. The CPUthen communicates with the movable electromagnetic coil so that theelectromagnetic coil to be positioned over a region on the scalp of thesubject according to the selected one or more fMRI maps. Propertranscranial magnetic stimulation from the coil is then delivered to theregion on the scalp of the subject so as to induce a current to flow inthe brain, cause neuronal depolarization in the brain, and effectuate achange in the performance of the predetermined task by the subject. Thesubject can be a person or an animal. The system can be constructedwithin a frame that is portable. Alternatively, the system can have anarray of TMS coils, each being able to deliver TMS individually or incoordination.

These and other aspects will become apparent from the followingdescription of the preferred embodiment taken in conjunction with thefollowing drawings, although variations and modifications may beeffected without departing from the spirit and scope of the novelconcepts of the disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a flow chart schematically showing one method of using TMS toimprove cognitive performance according to an exemplary embodiment.

FIG. 2 shows an exemplary transverse structural scan of a subject.

FIG. 3 illustrates how a TMS is placed over a subject according to anexemplary embodiment.

FIG. 4 shows exemplary reaction times and error rates for one subject.

FIG. 5 illustrates a TMS in cooperation with a fMRI scan according to anexemplary embodiment.

FIGS. 6 and 7 schematize and scale exemplary relationships between themagnetic field of a TMS coil and induced currents v. brain activation,respectively.

FIG. 8 illustrates shows exemplary results relating to the relativepositions of TMS-induced thumb movement and a similar movement executedvolitionally.

FIG. 9 illustrates an exemplary image of the brain with the fMRIactivation in the motor cortex superimposed.

FIG. 10 illustrates how to use MRI to image the magnetic field of TMSaccording to an exemplary embodiment.

FIG. 11 shows the magnetic field of a TMS coil on surfaces at differentdepths according to exemplary embodiments.

DETAILED DESCRIPTION

Several exemplary embodiments of the invention are now described indetail. Referring to the drawings, like numbers indicate like partsthroughout the views. As used in the description herein and throughoutthe claims that follow, the meaning of “a,” “an,” and “the” includesplural reference unless the context clearly dictates otherwise. Also, asused in the description herein and throughout the claims that follow,the meaning of “in” includes “in” and “on” unless the context clearlydictates otherwise.

Overview

Recent researches suggest the potential of TMS technologies. Topper etal. have shown that stimulation over temporal lobe facilitates orimproves picture naming (Topper et al., 1998). Grafman et al. haverecently shown that stimulation over the prefrontal cortex, and not shamstimulation, improves analogous reasoning (Boroojerdi et al., 2001). Thesame NIH group has shown that 1 Hz TMS for 10 minutes can transientlysuppress motor cortex or visual cortex activity, for up to 20 minutesfollowing stimulation.

However, there has never been a systematic, large-scale attempt tounderstand these phenomena and hence to use the TMS technologies in realworld applications. This invention represents exciting improvements inthe field and provides methods and system for ways of delivering TMS toimprove performance. Several aspects, applications, and embodiments ofthe present invention are reviewed as follows.

In one application, prior to engaging in a task, a subject such as asoldier has TMS applied to the appropriate region, with improvedcognition for a short amount of time so as to improve the subject'sperformance in the task. A slight modification would be to haveintermittent stimulation while performing the task at low intensitiesthat does not interfere with cognition, which in fact improvesreasoning.

According to exemplary embodiments, this and other applications can berealized through:

-   -   1. Improvements in TMS technology as discussed below; and    -   2. A series of TMS studies and/or experiments performed        according to exemplary embodiments in healthy adults providing        novel methods, procedure(s) and discoveries:        -   a. A series of excitatory TMS over prefrontal or other            regions of the brain to improve cognitive reasoning for a            period of time at a first state of mind such as being awake;        -   b. Whether this improvement is measurable on tests            resembling real word conditions such as combat conditions            and whether it degrades accuracy;        -   c. Finding and optimizing use parameters for achieving this            and other effects;        -   d. Locating other regions where intermittent stimulation            might improve cognitive reasoning; and        -   e. Repeat all of the above in subjects who are in the second            state of mind such as sleep deprived.

In other words, according to exemplary embodiments, TMS and fMRI may beused to understand the neural circuits involved and to apply TMS atproper regions in order to produce these effects (Nahas et al, 2000b;George & Bohning, 2000; Bohning et al, 2000a; Bohning et al, 2000b; andBohning et al, 1998).

Thus, the present invention greatly advances the TMS field, withspin-offs in the use of TMS as a neuroscience tool, in the ability touse TMS in other cognitive applications, and in advancing TMS as apotential therapy for neuropsychiatric disorders. Some of thesespin-offs include:

-   -   Materials science—New types of TMS coils are made from new        materials that have different electrical conductivity and may be        made to stimulate deeper into brain than presently possible;    -   Size of TMS devices—New types of TMS coils are made in ways that        are smaller, without the inefficiencies that generate heat;    -   Arrays—A plurality of TMS coils are coordinated in an array to        stimulate multiple regions in precisely timed ways. Arrays may        be received in a helmet for portability. Such a helmet may have        many overlapping figure eight regions that are controlled from        an external device such as a central control center; and    -   Portability—In one embodiment of the present invention, the        stimulators; capacitors and energy source are able to be placed        in combat areas in a portable device without sacrificing other        functions.

Furthermore, among other things, the present invention demonstrates,using one representative task (such as the Sternberg), whether and howTMS at different use parameters can be used to improve performance.Interestingly, even in studies over the motor cortex, there has not beena synthetic systematic examination of TMS use parameters on a behavior.

In sum, the present invention has the potential to revolutionize thisvery promising young field of TMS applications.

In one aspect, the invention relates to a method of determining TMS UseParameters. The measures here are performance data while healthysubjects are performing the Sternberg (Study 1A1) and having TMSdelivered over candidate or control regions, at different TMS useparameters. Specifically, response time (milliseconds) and error ratesare measured. This will be done both at rest and with partial sleepdeprivation (4 hours of sleep) (Study 1A4).

A separate set of data contains the fMRI brain maps of regions activatedduring the Stemberg at baseline. These fMRI brain maps can be used toguide the TMS placement, as well as to determine the physical dimensionsof a man-portable TMS system that, for example, do not need to have eachsoldier perform an fMRI activation map at the field.

Another set of data contains the fMRI brain maps of regions activatedduring the Stemberg while TMS is being applied within the scanner (1A5).These maps may help in understanding how TMS is modifying the brainduring task performance, and to generate hypotheses about secondarysites where TMS might be applied in order to even further boostperformance.

Generation alone of these three data sets (behavioral dose response withfocused, image guided application; data on the variation across subjectsin the physical location of this function; data on how TMS applied at akey site modifies brain activity) represents a remarkable and neverbefore completed advancement for science.

In another aspect, the invention relates to provide several man-portableTMS coil systems. In one embodiment of the present invention, thissection of work provides three models of potential TMS systems. Usinghigh power computers, each design is tested using computer modeling forbasic design issues such as (weight, heat generation, internal stresses,the amount of induced electrical current it could deliver within thebrain), and the power needed to run such a system. This results in aseries of design drawings of several TMS options, and formal white paperdiscussions of each area under testing (coil, power systems, etc). Thedesigns can be optimized by optimizing the use parameters needed toimprove cognition—(e.g. frequency, intensity, total dose, temporalrelationship of TMS to task performance), as well as information derivedfrom the model testing.

Among other things, the present invention has several advantages overthe prior art as discussed below. Many of the prior art studies focusedon pharmacological agents to improve performance, with little focus onwhere in the brain the compound is acting to improve performance. (Itwas interesting to note the general level of acceptance from militaryspokesman about the preference for non-pharmacological (i.e. TMS) CAPboosts over pharmacological approaches). On the other hand, many groupsproposed using functional brain imaging (PET or fMRI) to understand CAPvariables, but without discrete methods of acting on this circuit orsystems level knowledge. This invention is unique in that it directlytranslates systems level circuit findings from functional brain imaging,and then uses this knowledge to apply TMS to improve performance.

There are others who are proposing to use TMS in other applications.Importantly, the other proposals lack the design and testing elements ofhow to translate TMS into real world such as war fighter applications.Their approaches also focus on understanding sleep deprivation effects,while this invention has improved baseline or near baseline functioning.

Thus, the present invention is unique and highly relevant to the CAPSmission. One aspect of the present invention is to determine if TMS canboost performance on a sleep-deprivation sensitive task at baseline (orunder minimal degradation of performance), and then build a system thatmay allow this to be translated to the field.

In one embodiment of the present invention, fMRI image is used to guideplacement of the TMS coil so that the TMS coil is located at animportant region for the behavior. This maximizes the efficiency offinding performance enhancing TMS use parameters. Another aspect of thepresent invention involves examining the fMRI activation maps anddetermining probabilistic rules for TMS application, which may solve howone can translate these initial image guided effects with a simpler touse formula for large-scale production.

In sum, the present invention provides a revolutionary new approach toboosting cognitive performance, TMS, both at baseline and thenpotentially during periods of sleep deprivation. It uses high-techfunctional brain imaging and frameless stereotaxy to explore TMS useparameters over fMRI identified critical regions, and then uses a veryunique technology, interleaved TMS within an fMRI scanner, to fullyexplore potential ways of using TMS to boost performance.

Methods and System for Determining TMS Use Parameters

According to an exemplary embodiment, a series of TMS studies orexperiments may be conducted with the goal of determining whether TMScan enhance cognitive performance. The task that is used for thesestudies is the Sternberg task. This is chosen because it is easilyperformed, with a large body of literature, is stable over time andlargely immune from learning and order effects, and is sensitive tochanges in sleep, with measurable decreases in task performancefollowing sleep deprivation. Alternatively, other tasks can be chosenand/or used.

Determining TMS use parameters involves a series of TMS studies in theBSL and the CAIR 3T fMRI scanner, specially built for interleavedTMS/fMRI studies. The studies flow logically from one to the next, andare linked one on the next, although only 1A3 is truly conditional onprior results. They involve a common task, and a common method ofdelivering TMS to a particular region. The different studies are labeledas follows:

-   -   1A1—TMS during Sternberg; 30 subjects    -   1A2—TMS preceding Sternberg; 30 subjects    -   1A3—Replication and refinement of TMS effects; 60 subjects        (conditional)    -   1A4—Testing TMS effects with minor sleep deprivation; 60        subjects    -   1A5—Using interleaved TMS/fMRI to understand TMS effects and        find synergistic stimulation (20 subjects)    -   2A6—Using previously acquired fMRI scans to determine the        probabilistic method of applying TMS in a man-portable system    -   2A7—Testing whether probabilistic TMS placement is as effective        as fMRI guided    -   2A8—Testing whether similar effects are found in women.        Note that the number of subjects for each study can be modified        to include less or more subjects.

These studies are performed according to the embodiments of the presentinvention. Most of these studies involve methods recently worked outaccording to the present invention as illustrated in FIG. 1, which isdiscussed in detail below.

fMRI Scan. Within a 1.5 Tesla Philips MRI scanner, subjects were given ahigh-resolution structural MRI scan, followed by an echoplanar BOLD fMRIscan. During the fMRI scan, subjects had their heads constrained andwere able to view stimuli through MRI compatible 3-D goggles. They werealso able to respond to stimuli using a two-button response pad.Subjects were then shown the Sternberg task, or a control task includingseeing objects and responding to their physical location. The task andcontrol stimuli were presented in block designs of 26 seconds each,alternating over 10 minutes. Subjects were trained on the Sternberg taskprior to MRI scanning.

Image Data Analysis. Images were then transferred from the Philips to acomputer system such as the MUSC MAIAL Sun systems. There they wereinspected for artifacts, and corrected for motion across the 10 minutes.They were spatially and temporally smoothed using SPM within thesoftware MEDx. Staying within the person's own brain space (that is, nottransforming the data to a common brain space), t-tests were performedon the data to discern brain regions that were significantly more activeduring the Sternberg task than during the control condition. Regionsthat were significant at the p<0.001 level were then subjected to acluster analysis of p<0.05. These functional difference maps were thenoverlaid on the same person's structural MRI scan. The MUSC MAIAL hasthe ability to perform this series of steps in less than 24 hours. FIG.2 shows a transverse structural scan of a subject. Also shown are thebrain regions that are significantly more active while performing theSternberg compared to the control task (p<0.001 for display).

Frameless Stereotaxy. Within the BSL—The MUSC BSL is a beta test sitefor a frameless stereotaxy system such as one developed at McGillUniversity (Brainsight). These merged structure/function Sternbergimages are then transferred to the BSL Brainsight system. The subject isthen placed in a modified dental chair with passive head immobilizationsystem. The subject's brain is then stereotactically linked to the fMRIimage. The TMS coil is then placed over the subject's brain region,overlying the prefrontal area of maximal activation during the Sternbergminus control conditions as shown in FIG. 3. The TMS coil is alsopositioned over a region in the secondary occipital cortex not activatedin the fMRI images.

Sternberg Testing with TMS using different use parameters. Then, withthe TMS coil positioned over the candidate region or control region, ina randomized, counterbalanced manner, the subject performs the Sternbergwith TMS applied at different use parameters. FIG. 4 shows the reactiontimes and error rates for one subject who was stimulated over theprefrontal or occipital regions, each at high frequency (5 Hz) or lowfrequency (1 Hz), all at 110% of MT.

Follow-up Testing using the Interleaved TMS/fMRI technique. Once a TMSuse parameter is found that has a significant positive effect, thensubjects can be placed within the fMRI scanner as shown in FIG. 5, andwill perform the Sternberg task, with and without TMS applied to theregion. This allows an understanding of how TMS is acting to improvebehavior, and it may also identify secondary sites where TMS might beapplied with synergistic effects.

Applicants have spent several years reasoning through the most efficientmethods for rationally determining how to apply TMS in cognitiveparadigms. The method described herein shows the approach that theapplicants determined as the most logical, and the most efficient, atdetermining how to use TMS to modify cognition and improve performance.This individual fMRI based method of TMS placement, although technicallycomplex, completely solves the issue of where to apply the TMS. Withthis method, there is no question that the TMS is being delivered at theappropriate location. One can then begin a rational dose findingexploration. When specific dose or use parameter effects are found, thesame images that were used to guide the TMS placement in individuals canbe examined for probabilistic rules about where to apply TMS short ofwithin individual fMRI guidance.

Several studies or experiments performed according to exemplaryembodiments involving TMS delivered over fMRI identified regions to testif there are frequencies that enhance performance are now described inmore detail.

Subjects: For all experiments in this aspect of the present invention,the applicants recruit healthy young men (age 18-35), with the followinginclusion and exclusion criteria: No history of major head trauma orseizures; Medically healthy; No brain diseases; No metal objects intheir bodies prohibiting an MRI scan; No history of Substance Abuse;Urine drug screen negative.

Subjects are studied while free of alcohol or coffee for the day, in anon-sleep deprived state.

Also, several studies presented here are not involving female subjects.This has several advantages. First, there may be gender differences inregional brain activity and response to TMS. We would have toimmediately double our sample sizes and all dosing work. Further, brainexcitability and response to TMS changes slightly over the menstrualcycle, and we would need to perform studies in women timed inconjunction with the menstrual cycle. However, the methods and systemsdescribed herein can be applied to female subjects.

Subjects are invited to come to the BSL for initial screening. Therethey may give written informed consent, undergo a history and physicalexamination, undergo minor initial cognitive testing, be trained on theSternberg, and may provide a urine sample for drug screen.

On the second visit they may then have an fMRI brain scan (3.0 Tesla,Philips MRI scanner). This gives a high quality structural scan forBrainsight registration, and gives circuit information about Sternbergtask performance. This information can be processed in near real-time(24 hours) in the MAIAL, using MEDx and SPM. This generates anactivation map within each individual, merged onto that person's brain.

Two days later they return to the BSL where they will then participatein the following TMS techniques. Motor threshold is determined usingstandard techniques. In the following, several experiments aredescribed:

Study 1A1. 30 subjects, each studied twice TMS During the Stemberg. In acomplex, 6-hour study, subjects have the Magstim figure eight coilplaced over the prefrontal regions identified on MRI scanning. TMS isdelivered in the following matrix, with the following 3 variables tested(intensity, frequency, and region): The intensities tested will be—90,110, 120% of MT. The frequencies tested are 1, 5, 10 Hz. Other frequencyvalues can also be chosen. All epochs last about 10 minutes, with a10-minute rest. This gives 3×3×2=18 combinations of these variables.18×20 minutes=360 minutes (or 6 hours). Studies normally start at 8 amand proceed for 2, 3-hour blocks, with a 30-minute lunch break inbetween. A standard lunch is provided. Each subject then returns foranother similar day, separated by at least one-day rest. The order ofvariables are randomized and counterbalanced. Performing the samestudies twice on each individual can help reduce noise and standarddeviation and greatly enhance the ability to find TMS induced cognitiveimprovement, if it exists.

TMS is delivered regardless of whether the Sternberg stimulus is beingdisplayed, the interstimulus interval is on, or a response is needed.The reasoning for this is that if TMS needs to be that precisely coupledto stimulus processing, it is unlikely to have field applications.

Reaction Time and Error Rates: Data obtained for each subject averagedacross the two days by condition (e.g. profrontal 110% MT 5 Hz resultsfrom each day will be summed and averaged within each subject). Thesemean RT and error rates are analyzed using a 3 factor ANOVA testing forlocation (prefrontal or occipital control), frequency (1, 5, 10), orintensity (90%, 110%, 120% MT). Post-hoc tests are utilized to explorebehavioral trends within each factor.

Sample Sizes and Power: 30 subjects, each with two TMS day-longsessions, provide ample power to detect improvement in Sternbergperformance. Note that if positive effects are found, these are subjectto later replication, so this sample size is designed to be able toidentify an effect, if it exists. This can be tested later forreplication. Sample sizes of 20-30 have been used in the literature toshow TMS effects on cognition of 10% or more. A formal power analysisreveals that if there is a 5% variation of Stemberg performance acrossthe variables, a sample of 30 subjects will have an Alpha of 0.05 and a95% power to detect a 5% improvement as a function of one of the 3factors (intensity, site, frequency). Further, for all effects found,these are tested for replication in a separate cohort (See Study1A3below).

Study 1A2: 30 subjects are split in 2 groups. TMS before Sternberg isbeing performed. Data from the Queen Square group over motor cortex andfrom Cohen and colleagues over both motor and occipital cortex haveshown that TMS can be delivered before a cognitive task, with resultinglasting effects for up to an hour. In many ways, delivering TMS before abehavior in a real world setting such as a combat setting isadvantageous to performing it during the behavior.

In a similar, 6 hour study, 15 initial subjects have the Magstim figureeight coil placed over the prefrontal site or the occipital cortex. TMSare delivered in the following matrix, with the following 3 variablestested (intensity, frequency, region): In this study, TMS is deliveredduring the 10 minutes immediately preceding the Stemberg task. Therewill be no TMS during the actual task. Rather, subjects are examined forlasting effects of TMS delivered before the task. The intensities testedare—90, 110, 120% of MT. The frequencies tested are 1, 5, 10 Hz. Allepochs will last 10 minutes, with a 10 minute rest. This gives 3×3×2=18combinations of these variables. 18×20 minutes=360 minutes (or 6 hours).Studies normally start at 8 am and proceed for 2, 3-hour blocks, with a30-minute lunch break in between. Each subject then returns for anothersimilar day, separated by at least one day off. The order of variablesare randomized and counterbalanced. Performing the same studies twice oneach individual helps reduce noise and standard deviation and greatlyenhances the ability to find TMS induced cognitive improvement. Again,other sets of testing parameters can be utilized to provide new set ofdata.

Results are analyzed in the first 15 subjects using the 3 factor ANOVAdescribed above. These variables can be examined and predict the useparameters in the next 15 subjects. In this study, the same methods asabove are used, except the frequency and intensity with the best effectare utilized, and a new variable of time preceding task is introduced.Thus there is one frequency and one intensity. TMS will be delivered forvariable amounts of time (10 min, 20 min, 30 min) and variable timesbefore the Sternberg (10 min, 20 min, 30 min).

Again, these response data (reaction time, error rate) are analyzedusing repeated measures ANOVA examining for dose and time from TMS.

Study 1A3: Study 1A3 is designed to, among other things, examinereplication and refinement of TMS effects. If significant effects arefound with either Study IA1 (During) or 1A2 (Preceding) or both, anattempt is made to replicate these in an independent cohort and examineTMS effects with parameters in the same neighborhood. Thus, theseconditional studies in 30 subjects are designed to replicate and extendany findings that might be observed in the initial studies. To do so, anadditional 30 subjects are recruited and TMS are performed either duringor before the Sternberg so as to explore the neighboring use parameters.For example, if prefrontal TMS 1 Hz, MT were found to enhance theSternberg during performance, one would retest this, and add theconditions of 1.5 Hz, 0.5 Hz, 90% MT and 110% MT.

These studies (1A1, 1A2, 1A3) are designed to be performed in subjectswho are not sleep deprived. One can question, however, whether effectsfound in these subjects are able to be applied to the CAP mission ofimproving performance during sleep deprivation, which is for eachsubject a different state from the state where a subject is not sleepdeprived. It is possible, although unlikely, that a TMS effect seen innon-sleep deprived conditions might have a paradoxical effect in sleepdeprived conditions. More likely is another scenario where TMS is ableto have little or a marginal effect under optimum conditions, but agreater effect in slightly degraded conditions. The following twostudies are similar to the above studies, but differ in that subjectsare admitted overnight to a test facility such as the GCRC and thenawakened at 3 am, thus ensuring that they are partially sleep deprivedduring the TMS session the following day.

Study 1A4 (during and before Sternberg, with partial sleep deprivation):60 subjects. The same studies as described above are done with subjectswho are partially sleep-deprived. That is, subjects are admitted to theGCRC and awakened at 3 am, and then have testing done on the dayfollowing sleep deprivation. They will be sent home for a normal night'ssleep, then readmitted the following night and retested, thus having asecond day of repeated mild partial sleep deprivation. These studies areneeded even if large performance enhancing TMS effects are seen in theearlier, non-sleep deprived studies. These subjects would be run in thisstudy for safety and to make sure that TMS stimulation parameters thatare helpful in non sleep-deprivation are not problematic or worsening insleep deprived individuals.

Study 1A5: 20 subjects. Study 1A5 utilizes TMS within the fMRI scannerto examine effects found. When significant effects are found in any ofthe Studies 1A1, 1A2 and 1A3, as they do, TMS is then performed withinthe fMRI scanner at the location with use parameters found to have abehavioral effect. This study provides valuable information about howTMS is producing its effects, and might indicate other regions where TMScould be applied in a synergistic fashion in addition to prefrontalstimulation. This study may also aid greatly in understanding how focalor diffuse the TMS application might be in order to achieve behavioraleffects.

In doing so, TMS is administered within the fMRI scanner at the useparameters found in the earlier studies, while subjects are performingthe Sternberg task. Data analysis is performed similar to that used todetermine the optimum spot for TMS placement.

Study 2A6: To answer how precise must the placement be to achieveenhancement in performance, Study 2A6 is designed to perform image dataanalysis. Thus, in this study, no new subjects, but examination ofimaging data previously acquired. If performance effects are found usingthe very precise anatomical precision method, there is a need to see ifTMS can be done in a less precise anatomic location method. Thefunctional imaging scans obtained in the earlier parts of the Studies1A1-1A5 will be analyzed in MedX to generate a probabilistic rule forhow imprecise to place the TMS coil and still improve performance. Thismay involve examining the range of regions identified as critical inSternberg performance across subjects and then morphing individual brainscans into a common brain space.

Study 2A7: Among other things, study 2A7 is designed to test whetherprobabilistic TMS placement is as effective as fMRI guided. In thisstudy, the rule generated in Study 1A6 is directly tested in a newcohort of 30 subjects. The use parameters are those previouslyidentified as optimum for maximizing effects. The variable to beexplored here is location of the TMS coil—fMRI guidance, versus therule-based algorithm identified above. In addition to a direct test ofthe proposed algorithm, TMS is systematically delivered in 1-mmincrements away from the MRI identified region, to assess how imprecisethe TMS application might be.

Study 2A8: Among other things, Study 2A8 is designed to test whethersimilar effects are found in women. In one embodiment, the test groupincludes 30 women. In particular, before a TMS system could be used inthe military, it would be important to determine if similar effects areseen in women. Thus, in 30 women screened as above, they would have TMSapplied in the manner determine in Study 1A1-1A5 testing to have optimumeffects.

An Experiment:

In yet another experiment/study, a plurality of subjects was dividedinto two groups. The first group contained 6 subjects with clearimprovements in the Stemberg (RT) with the prefrontal TMS. The secondgroup contained 6 subjects with clear worsening. Each group then wasmonitored for each subject's activity during the Stemberg within thefMRI, wherein no TMS was applied. Data was obtained and then analyzed toshow that the TMS prefrontal improvers (the first group) used prefrontalcortex and cingulated during the Stemberg; in contrast, those in thesecond group whom TMS did not improve RT, or even worsened it, did notuse prefrontal and cingulated but instead used parietal and visualcortex (and/or maybe basal ganglia). Thus, different people usedifferent neural circuits, both at rest and when sleep deprived, andthese circuits can be identified and selected by fMRI, which in turnallows TMS to be used to either restore function or train or refraincircuits according to the present invention.

B. Designing A Portable TMS System

Another aspect of the present invention relates to a portable TMS systemthat can be used in real world situations to enhance cognitiveperformance. To achieve effective TMS with a man-portable system, thereare 3 major considerations: 1) physical size of the TMS “coil”, 2)device positioning, and 3) power requirements. With all three, there areconflicting demands on the system. A small sized “coil” would be moreportable, but, if too small, might not be effective at stimulating thebrain. A system that would allow the coil's position to range over anarea would make it possible to accommodate the varied brain anatomy ofdifferent people, but would likely be more bulky and complex. Increasedpower demands almost always introduce complexity and weight, butdecreasing the power of the system would also likely mean that greateraccuracy would be required in coil positioning.

Improved understanding of the absolute requirements for effective TMSgained in practicing the present invention provides clearly definedconstraints for the design, and innovations in materials and/or design,though not eliminating these conflicts, may reduce them so that apractical man-portable TMS system is achievable according to the presentinvention.

A portable TMS system according to an exemplary embodiment, takes intoconsideration at least some of the following:

-   -   1) TMS anatomical characterization, i.e., where in the cerebral        cortex does neuronal discharge occur: a) sulcus, b) crown of        gyrus, c) transition zone, or d) a combination of them;    -   2) TMS physical characterization, i.e. functional relation        between TMS “coil” field and degree of neuronal activation;    -   3) TMS “coil” coverage requirements, i.e. a) localized or        nonlocalized stimulations, b) single or multiple stimulation        sites, c) field profile requirements, full widths at half        maximum (FWHM): Wx,Wy,Wz;    -   4) TMS “coil” positioning requirements, i.e. must the coil        position be adjustable to accommodate different brain anatomy,        range of movement: Rφ, Rθ, Rr;    -   5) Magnetic field characteristics of concept coils: standard        figure-8, modified figure-8, programmable lattice, spinning        magnet, moving magnet, and phased-array;    -   6) Conductivity model of human brain;    -   7) Electric field characteristics of concept coils: standard        figure-8, modified figure-8, programmable lattice, spinning        magnet, moving magnet, and phased-array;    -   8) Induced current characteristics of concept coils: standard        figure-8, modified figure-8, programmable lattice, vibrating        permanent magnet, and phased-array;    -   9) TMS induced current measurement project: To determine if TMS        induced currents might be mapped in-vivo;    -   10) Power requirements for TMS stimulator;    -   11) Preliminary design for reduced power TMS stimulator; and    -   12) Concepts for man-portable power supply.

Some aspects of design characteristics of a portable TMS systemaccording to an exemplary embodiment are discussed in more detail below.

Magnetic Field and Induced Currents Versus Brain Activation

Better data is needed on the relationship between the magnetic field ofthe TMS coil and the induced currents, and, in turn, the anatomy ofcerebral cortex and the actual depolarization of neurons in cerebralcortex. FIGS. 6 and 7 schematize and scale these relationships fororthogonal orientations of a standard figure-8 TMS coil to help morequantitatively define some of the factors involved in TMS, factors whichwill likely constrain the design of a man-portable TMS system. Thisprovides information about where one needs to stimulate, how focal thestimulations needs to be, and the preferred direction of the inducedelectric fields. It gives information on the variation in brain anatomybetween individuals. Combining this information, one can get an idea ofthe required size of the “coil” and if it will be necessary to positionit differently for different brain anatomies, i.e., if one size fitsall, or if one needs to custom fit the “coil” to each person. It alsoprovides information about the field intensities that must be produced,and how they must be directed relative to the relevant structures in thebrain. This is important for deciding on a configuration for the coil aswell as the power requirements.

Data about size and location of TMS Performance related activations andcoil position relative to activation are also needed. Data may come fromBrainSight data from Studies 1A1-1A5. This information tells one aboutthe importance of position, i.e., is the effect sensitive to position,or can a generalized stimulation be used.

Data about spatial variation of relevant brain structures are obtainedto tell one whether a single configuration is sufficient, or, at theother extreme, if the coil must be customized for or adaptable to eachindividual. This largely involves a comprehensive literature review ofpublished data (human and animal) and then examination of the Brainsightdata being collected in Study 1A2-1A5 subjects.

Data about magnetic field vector at activation site can be obtained fromtwo ways. First, phase maps and TMS/fMRI data from past studies areutilized: Using data from previous TMS/fMRI studies over motor cortex,the relative displacements of TMS coil, motor cortex, and fMRIactivation will be obtained. These will then be combined withsimulations of the TMS coils magnetic field and knowledge of the anatomyof motor cortex to gain a better understanding of the relationshipbetween magnetic field and cerebral cortex for optimum stimulations.FIG. 8 shows exemplary results according to the present invention. Therelative positions of TMS-induced thumb movement and a similar movementexecuted volitionally are determined (Bohning et al., 2000). Coil andmagnetic field distributions may be added to complete the picturerelating activation and magnetic field. FIG. 9 shows more of thispreliminary work on this problem, an image of the brain with the fMRIactivation in motor cortex superimposed and an arrow indicating thedirections and magnitude of the magnetic field at the center of the fMRIactivation.

Additionally, the computed B-field of the coil combined with BrainSightData from Studies 1A1-1A5 can be utilized. As in the above case, thiscan provide data about the relative displacements of the TMS coilstimulation and the area of activation in motor cortex. Though it maynot show the area of activation as does fMRI activation, it can show theposition of the TMS coil position at which the maximum motor evokedpotentials (MEPs) were induced relative to brain anatomy. Thisfacilitates one to tie magnetic field to area of cerebral cortex inwhich neuronal discharge occurs as well as the anatomical structure.

Magnetic Field, Electric Field and Induced Current Simulations forDifferent Coil Designs

The field patterns of the different coil configurations are a majorfactor in either eliminating a particular coil design or selecting itfor further development. In one embodiment, the coil is capable ofstimulating the desired area(s) effectively, and if focal rather thandiffuse stimulation is desired, it must not stimulate other areas.

Field Simulations are performed for standard figure-8, modifiedfigure-8, programmable lattice, vibrating “crescent” permanent magnet,and phased-array. The simulations will be similar, except that theelectric field induction is caused by the movement by the vibratingpermanent magnets, rather than by current pulses as in the figure-8 andlattice coil. Alternatively, field simulations can be conducted oncomputer models.

B-field phase maps are utilized as well. The coils magnetic fieldpattern can be measured using MRI phase maps to check the computedmagnetic fields (Bohning et al., 1997). FIG. 10 illustrates theprinciple, and FIG. 11 shows brain images on which a surfaceapproximately 2 cm below the scalp, about the depth of most TMS and atdifferent depths.

MRI segmentation into gray and white matter and CSF for conductivityvolume map are used in the present invention. Moreover, phase map fMRItechnique is used to advance understanding in this area.

Induced E-Field Simulations:

The induced E-field may be computed in a plane parallel to a simplefigure-8 coil and homogeneous medium. It would be necessary to do thisfor a volume encompassing the areas of the brain to be stimulated andextend the calculations to, at least, a three component model of braintissue, i.e., gray and white matter and CSF.

Induced J-Currents Simulations:

Induced currents actually cause the neuronal discharge associated withthe activation.

Induced E-Field and Induced J-Currents Versus Brain Anatomy Mapping:

It has been estimated that the transmembrane current flow needed todepolarize the membrane is caused by the spatial derivative of theelectric field along the axon, dE/dx, (Reilly 1992; Abdeen and Stuchly1994; Garnham et al. 1995) and that the peak spatial derivative neededto achieve stimulation is approximately 5 kV/m² (Rudiak and Marg 1994).Our simulations along with previously acquired data and data from theabove studies should make it possible for us to check and extend theseobservations.

Power Requirements:

Based on the strength-duration relation for neuronal depolarization,$\left. \begin{matrix}{{Q(t)} = {Q_{0}\left\lbrack {1 + \frac{\Delta\quad t}{\Delta\quad t_{0}}} \right\rbrack}} \\{{J(t)} = {J_{0}\left\lbrack {1 + \frac{\Delta\quad t}{\Delta\quad t_{0}}} \right\rbrack}}\end{matrix} \right\}\quad$where Q₀=minimum threshold depolarization charge density for nonleakymembranes

-   -   J₀=rheobase, the minimum stimulus current density that can        attain threshold at infinite duration    -   Δt₀=the strength-duration time constant (chronaxie) (≈150 μs,        Barker et al., 1991) and our estimates of induced currents, we        will attempt to adjust the TMS pulse waveform to increase        depolarization efficiency and reduce power consumption.        Moving Magnet Induction

Though there are no resistive losses due to large currents, the “moving”magnets have to be moved in approximately a quarter of a millisecond.This will require some sort of electromechanical device, which itselfwill consume power, to overcome the coil's inertia, move it a shortdistance and then return, which could be cumbersome and fragile. Amagnet spinning at high speed, would require neither a large current,nor the generation of the forward and backward impulses of a pulsedsystem, but would require power to bring the spinning magnet up to speedand keep it there and would generate current continuously not pulses.There would also be a problem with the gyroscopic effect of any magnet,large enough to stimulate the brain, spinning at high speed. Inaddition, there is no data on the stimulation pattern of such a TMS“coil”, so extensive simulations would be necessary. However, theseconcepts should not be rejected out of hand, and the information gainedthrough the associated simulations would increase our understanding ofthe magnetic fields and induced currents of any design.

Electronic Induction

Though the absolute power requirements will only be know once the TMSperformance studies have been completed, to tell us the frequency andduration of stimulation, it is certain that we will be aiming at theabsolute minimum power per pulse required for effective stimulation.This can be explored by 1) reducing resistive and inductive power lossin the “coil” and 2) altering pulse waveform for more efficientexcitations, and resonant stimulator power. Resistive and inductive lossreduction will be sought through the uses of new “coil” materials, e.g.,silver and/or room temperature superconductors, and “coil” conformationchanges to confine losses to those associated with currents induced inthe brain. We also explore the use of an impedance matching gel filledliner to take shape of head to see if this may improve currentdistribution or reduce power consumption. The shorter the stimulatingwaveform, the less power that is required to induce neuronal discharge,hence we design a stimulator power supply that puts out shorterwaveforms, and, operates in a “resonant” mode to recapture the returningpulse.

Stimulation Control

According to exemplary embodiments, for stimulation control, thefollowing are provided and modeled: a means for controlling the TMSstimulation, stimulation pattern control, and programmable lattice coilposition control, which can be merely a means of activating the latticeelements to create a coil of a particular size at a particular position,or, it can include a test sequence for customizing the coil toaccommodate individual anatomy.

Coil Designs, i.e., Possible Solution Devices

The following designs are modeled according to exemplary embodiments:

-   -   Standard figure-8;    -   Modified figure-8:    -   Programmable Lattice;    -   Vibrating magnets; and    -   MEMs—Micro-electromechanical Devices—Assess possible application        in cortical stimulation phased array.

According to exemplary embodiments, several (at least 3) prototypes ofthe portable TMS system are produced and tested in conditions graduallyapproaching actual combat. The initial testing would be done in the BSLusing military simulator computer programs. If these were successful,then testing would be performed in the actual field.

For each prototype delivered, the device is tested for performancecapabilities (e.g., Tesla generated, heating, weight, etc.). Then, theprototype is used in the BSL on subjects and record performance behaviorand other side effects.

Prototype 1 will be performance tested in the BSL, likely using flightsimulators or submarine simulators, as well as the Sternberg task, byusing likely simulators would be those involving long range flightsimulators, or Advanced SEAL Delivery Systems.

Prototype 2 would be field tested in an armed services testing lab, andPrototype 3 would be tested in actual field conditions. Testing would bedone under optimum and mildly sleep deprived conditions. Initial testing(prototype 1) would be done on healthy young men or women. Later testingwould involve trained warfighters. Prototypes would be evaluated as wellfor safety (neuropsychological and behavioral as well as for the deviceitself).

In summary, the present invention provides, among other things, thefollowing:

-   -   1) fMRI images: In one example, a series of fMRI activation maps        in 120 healthy young men while performing the Sternberg task.        These maps would show how much the functional localization of        the Sternberg task varies across individuals.    -   2) TMS use parameter dose response performance data, both at        baseline and after partial sleep deprivation; a detailed dose        finding study of whether and how TMS might modify Sternberg        performance if delivered during the task or before it. These TMS        effects would be understood both at baseline and under        conditions of partial sleep deprivation.    -   3) Interleaved TMS/fMRI maps showing how TMS applied at key        regions modifies circuit behavior and changes performance.    -   4) Design maps and models of Man-portable TMS Systems: These        would be detailed and able to be presented to industry for        prototype construction.    -   5) 3 working prototypes of a man-portable TMS system.    -   6) Detailed data on whether and how these systems perform in        simulator and field testing.    -   7) Improved understanding of how to create TMS systems for mass        use without the need for individual fMRI guidance of TMS        placement.    -   8) Understanding of whether TMS works at these parameters in        women as well as men.

This body of work has the potential for revolutionizing the approach toenhancing cognitive performance by focusing on brain circuits andminimally invasive brain stimulation.

While there have been shown preferred and alternate embodiments of thepresent invention, it is to be understood that certain changes can bemade in the form and arrangement of the elements of the system and stepsof the method as would be know to one skilled in the art withoutdeparting from the underlying scope of the invention as describedherein. Furthermore, the embodiments described above are only intendedto illustrate the principles of the present invention and are notintended to limit the scope of the invention.

Moreover, the texts and drawings of the Appendix are incorporated intothe application by reference as an integral part of the application.Additionally, the documents listed in the Appendix are incorporated intothe application by reference.

1. A method for using transcranial magnetic stimulation to enhancecognitive performance, comprising the steps of: locating at least oneneural circuit in the brain of a subject, which is activated when theperson performs a predetermined task; positioning an electromagneticcoil over a region on the scalp of the subject corresponding to the atleast one neural circuit in the brain of the subject; and delivering atranscranial magnetic stimulation from the coil to the region on thescalp of the person to incude current to flow in the brain that causesneuronal depolarization in the brain and effectuates a change in theperformance of the predetermined task by the subject.
 2. The method ofclaim 1, wherein the subject is a human being.
 3. A method for usingtranscranial magnetic stimulation to enhance cognitive performance in aplurality of subjects, comprising the steps of: dividing the pluralityof subjects into groups, subjecting each of the groups into a firststate and a second state, locating at least one neural circuit in thebrain of a subject in the group corresponding to one of the first stateand the second state, which is activated when the subject performs apredetermined task under one of the first state and the second state,positioning an electromagnetic coil over a region on the scalp of thesubject corresponding to the at least one neural circuit in the brain ofthe subject, and delivering a transcranial magnetic stimulation from thecoil to the region on the scalp of the subject to induce a current toflow in the brain that causes neuronal depolarization in the brain andeffectuates a change in the performance of the predetermined task by thesubject under one of the first state and the second state.
 4. The methodof claim 3, wherein the subjects are human beings.
 5. The method ofclaim 3, wherein the first state is a state in which a subject is atrest, and the second state is a state in which a subject issleep-deprived.
 6. The method of claim 3, wherein functional magneticresonance imaging maps are used to identify different neural circuitsassociated with different subject on a state, wherein the neuralcircuits are activated while a predetermined task is performed.
 7. Themethod of claim 6, wherein transcranial magnetic stimulation isdelivered to proper neutral circuits to restore and/or retrain thecircuits to enhance the performance.
 8. A method of using transcranialmagnetic stimulation to enhance cognitive performance in at least onesubject, comprising: during a behavior individualized imaging of atleast one cognitive neural circuit, locating the at least one cognitiveneural circuit, individually positioning an electromagnetic coil over aregion on the scalp of the subject corresponding to the at least onecognitive neural circuit, and delivering a stimulation through theelectromagnetic coil to the at least one cognitive neural circuit toaffect the behavior related to the at least one cognitive neuralcircuit.
 9. The method of claim 8, wherein individualized imaging can beperformed by a functional magnetic resonance imaging scanner.
 10. Themethod of claim 8, wherein the electromagnetic coil is interleaved witha transcranial magnetic stimulation system to provide synergisticstimulation(s).
 11. A system for using transcranial magnetic stimulationto enhance cognitive performance in at least one subject, comprising:means for locating at least one neural circuit in the brain of asubject, which is activated when the subject performs a predeterminedtask, an electromagnetic coil that can be positioned over a spot on thescalp of the subject corresponding to the at least one neural circuit inthe brain of the subject, and means for delivering a transcranialmagnetic stimulation from the coil to the spot on the scalp of thesubject so as to induce a current to flow in the brain, cause neuronaldepolarization in the brain, and effectuate a change in the performanceof the predetermined task by the subject.
 12. The system of claim 11,wherein the locating means includes a functional magnetic resonanceimaging system that can be utilized to scan and generate maps of theinterested neural circuits so as to locate proper neural circuitsresponsible for a predetermined task.
 13. The system of claim 11,further comprising a computer having a CPU and one or more memorydevices to coordinate the operation among the different parts of thesystem, optimize the operation parameters, and facilitate thetranscranial magnetic stimulation delivering.
 14. The system of claim13, wherein the operation parameters are transcranial magneticstimulation parameters.
 15. A portable system for using transcranialmagnetic stimulation to enhance cognitive performance in at least onesubject, the system comprising: a CPU; an energy source electricallycoupled to the CPU; a database in communication with the CPU and havingfunctional magnetic resonance imaging (fMRI) maps of neural circuitscorresponding to a plurality of tasks stored therein; and a movableelectromagnetic coil electrically coupled to the energy source and incommunication with the CPU, wherein when a subject is to perform apredetermined task, the CPU selects one or more fMRI maps of one or moreneural circuits from the corresponding to the predetermined task fromthe database and causes the movable electromagnetic coil to bepositioned over a region on the scalp of the subject according to theselected one or more fMRI maps, and the movable electromagnetic coildelivers transcranial magnetic stimulation to the region on the scalp ofthe subject so as to induce a current to flow in the brain, causeneuronal depolarization in the brain, and effectuate a change in theperformance of the predetermined task by the subject.
 16. The system ofclaim 15, wherein the energy source is a battery.
 17. The system ofclaim 15, wherein the database is associated with a memory device of theCPU and/or a separate memory device.
 18. The system of claim 15, whereinthe subject is a person.
 19. The system of claim 15, wherein the subjectis an animal.
 20. The system of claim 15, wherein the system isconstructed within a frame that is portable.
 21. The system of claim 15,wherein the system comprises an array of transcranial magneticstimulation coils, each being able to deliver transcranial magneticstimulation individually or in coordination.